Immunosuppressant drugs have been used for purposes of preventing adverse immune responses, either a rejection of a transplanted organ, or an attack on the patients own body by its own immune system caused by an autoimmune disease, without unduly suppressing the ability of the patient's immune system to combat infection. Such immunosuppressants have included rapamycin [U.S. Pat. No. 5,694,950]; FK 506 [U.S. Pat. No. 5,365,948]; and cyclosporine.
With the advent of gene therapy, a need exists for methods of repeat administration of gene therapy vectors, such as viral vectors, exists. Methods are needed which are able to effectively overcome the body's normal immune response to gene therapy vectors such as viral vectors. In order to overcome the immunologic problems associated with repeat administration of adenoviral vectors, the use of broad immunosuppressants (Engelhardt et al., Proc. Natl. Acad. Sci. USA 91:6196-6200 (1994)) and cytoablative agents (Dai et al., Proc. Natl. Acad. Sci. USA 92:1401-1405 (1995)) to overcome the immune response of the host to first generation Ad vectors have been tested. Transient co-administration of an immunoglobulin, CTLA4-Ig, along with an intravenous injection of Ad vector expressing a non-immunogenic transgene product (human oc-I anti-trypsin) has been shown to lead to persistent transgene expression from mouse liver (Kay et al., Nat. Genetics 11:191-197 (1995)). CTLA4-Ig blocks the B7-CD28 pathway of T cell co-stimulation, which is required for optional activation of T cells. (Jenkins et al., Immunity 1:443-446 (1994); Lenschow et al., Ann. Rev. Immunol. 14:233-258 (1996)). Although adenoviral-specific antibody levels were reduced in CTLA4-Ig treated mice, the inhibition was not sufficient to allow secondary gene transfer via repeat administration of the vector under the conditions tested (Kay et al., Nat. Genetics 11:191-197 (1995)). Thus, many immunosuppressant molecules are not effective for gene therapy purposes in which persistent expression of a foreign transgene is desired. Accordingly, a need exists for methods of employing immunosuppressant drugs which are effective when used with gene therapy vectors.